Alpha-substituted beta-propiolactones



United States Patent '0 3,028,399 ALPHAqSUBSTITUTED BETA-PROPIOLACTONES Emilio Testa, San Simone, Vacallo, Ticino, Switzerland,

assignor to Lepetit, S.p.A., Milan, Italy No Drawing. Filed June 29, 1959, Ser. No. 823,334 Claims priority, application Great Britain July 17, 1958 4 Claims. (Cl. 260-3439) According to the process of the invention, one mole of a fl-aminopropionic acid is reacted with about 2 to about 3 moles of an alkali metal nitrite in dilute acetic acid at a temperature below 5 C. If the product does not precipitate in the course of the reaction, the mixture is extracted with a water immiscible solvent and the solvent removed. The residue'is the desired fi-lactone, which can be purified, if desired, through conventional procedures. For instance, the product may be distilled through a column if it is an oil, or recrystallized from a selected solvent if it is a solid substance. Yields are usually fairly high. The lactones of the invention are useful as intermediate compounds for the preparation of a number of industrial products. For instance, they may be hydrolysed to the corresponding hydroxy acids:

which are important intermediates in the synthesis of atropine and synthetic antispasmodics, as indicated in the British patent specification 709,585. The same hydroxy acids are starting compounds of our copending US. applications Serial Nos. 748,148, filed July 14, 1958 and 767,520, filed October 16, 1958, both now abandoned. These applications claim pharmacologically useful 5,5-disubstituted-tetrahydro 1,3-oxazine-2,4-diones. Examples of conversion of the lactones into the hydroxy acids are given hereinbelow.

Moreover, when treated with ammonia under pressure in a solvent, the fi-lactones are converted into the 2- acetidinones claimed in our copending US. applications Serial Nos. 731,635 and 731,637 both filed April 29, 1958, both now abandoned.

The following examples are illustrative of the invention.

EXAMPLE 1 a-Phenyl-a-Butylpropionolactone Into a solution of 11 g. sodium nitrite in 30 ml. water, previously cooled to 0 C., a solution of 10 g. a-phenyl-abutyl-fl-aminopropionic acid in 125 ml. aqueous acetic acid is gradually dropped taking care not to exceed 5 C. The mixture is stirred for 1.5 hours at 05 C., then it is extracted with three 100 ml. portions of ethyl ether. The extracts are combined, the solvent removed and the residue distilled collecting at 118-120 C./1 mm. Hg. Yield 7.5 g. (81%).

The obtained lactone may be hydrolysed to the hydroxy acid by heating it at about 100 for minutes in 5% sodium hydroxide. After cooling the solution is extracted with ethyl ether, the extract discarded, the water layer 3,028,399 Patented Apr. 3, 1962 ICC 2 made acidic with sulfuric acid and again extracted with ethyl ether. The organic solvent is removed and the residue treated with petroleum ether. The formed crystals are collected. Yield nearly quantitative. M.P. -78 C.

EXAMPLE 2 a-Phenyl-a-Ethylpropionolactone Into a solution of 9.6 g. sodium nitrite in 25 ml. water a solution of 10 g. a-phenyl-a-ethyl-fi-aminopropionic acid in 125 ml. 25% aqueous acetic acid at 0-5 C.'is gradually dropped. After stirring for additional 90 minutes the mixture is extracted with ethyl ether, the solvent is removed and the residue distilled collecting at 105 C. under 1 mm. Hg. Yield 7.3 g.

When hydrolysed with dilute sodium hydroxide as described in Example 1, the compound gives a-phenyl-aethyl-fl-hydroxypropionic acid, M.P. 9698 C.

EXAMPLE 3 u-Phenyl-a-Methylpropionolactone Into a solution of 9.6 g. sodium nitrite in 25 ml. water a solution of 10 g. a-phenyl-a-methyl-fl-aminopropionic acid in 125 ml. 25% aqueous acetic acid is gradually dropped at 0-5 'C. After stirring for an additional minutes at 05 C. the mixture is extracted with ethyl ether, the solvent is removed and the residue distilled collecting at 75-80 C. under 0.6 mm. Hg. Yield 7.1 g. (79% When hydrolysed with dilute sodium hydroxide as described in Example 1, the compound gives a-phenyl-amethyl-B-hydroxypropionic acid; M.P. 87-88" C.

EXAMPLE 4 a-Phenyl-a-Benzylpropionolactone Into a solution of 6 g. sodium nitrite in 25 ml. water there is gradually dropped a solution of 10 g. a-phenyl-abenzylfi-arninopropionic acid in 300 ml. 50% aqueous acetic acid and 1.3 ml. sulfuric acid (to dissolve the amino acid, poorly soluble in acetic acid). A precipitate forms. After stirring for 45 minutes at 0-5" C. the crystals are collected by suction and dried. Yield 6.5 g. (70% M.P. 124125 C.

When hydrolysed with dilute sodium hydroxide as described in Example 1 the product gives u-phenyl-a-benzylfl-hydroxypropionic acid; M.P. 191-193 C.

EXAMPLE 5 a-Phenylpropionolactone Into a solution of 40 g. sodium nitrite in 120 ml. water, previously cooled to 0, a solution of 20 g. a-phenyl-flaminopropionic acid in 400 ml. 25 aqueous acetic acid is gradually dropped without exceeding 5" C. The mixture is stirred 30 minutes at 0-5 then it is extracted with three 500 m1. portions of ethyl ether. The extracts are combined, the solvent removed and the residue distilled collecting at -100 C./1 mm. Hg. Yield 15 g. (83%).

When hydrolysed with NaOH as described in Example 1 this compound gives a nearly quantitative yield of tropic acid.

EXAMPLE 6 ,a-Diethylpropionolactone Into a solution of 12 g. sodium nitrite in 75 ml. water, previously cooled to O", a solution of 11.2 g. a,u-diethylfi-aminopropionic acid in 250 ml. 25% acetic acid is 3 EXAMPLE 7 a,a-Diprpylpropionolactone Prepared as described in Example 6 for the diethyl homologue. The product distils at 86-88/5 mm. Hg. Yield 84%.

EXAMPLE 8 a,u-Dibutylpropionolactone Prepared as described in Example 6 for the diethyl homologue. The product distils at 98-100/3 mm. Yield 82%.

I claim: l. A process for preparing B-lactones of the formula R1 \CO wherein R and R, are members of the class consisting of hydrogen, phenyl, alkyl and benzyl groups, which comprises mixing a flaminopi'opionic acid of the formula R CHINHZ R1 COOH wherein R and R have the above significance, with 2 to 3 equivalents of sodium nitrite in 25% aqueous acetic acid at a temperature below 5 C.

3. Process for preparing a fi-lactone of the formula phenyl C H:

which comprises mixing alpha-phenyl-alpha-ethyl-betaaminopropionic acid with two to three equivalents of an alkali metal nitrite in dilute acetic acid at a temperature below 5 C. v

4. Process for preparing a p-lactone of theformula which comprises mixing alpha-phenyl-alpha-methyl-betaaminopropionic acid with two to three equivalents of an alkali metal nitrite in dilute acetic acid at a temperature below 5 C.

References Cited in the file of this patent UNITED STATES PATENTS 2,449,994 Gresham et al. Sept. 28, 1948 2,739,158 Caldwell Mar. 20, 1956 FOREIGN PATENTS 709,585 Great Britain May 26, 1954 OTHER REFERENCES Adams (Ed): Organic Reactions, vol. VIII, Wiley, New York, N.Y., (1954), page 311. 

4. PROCESS FOR PREPARING A B-LACTONE OF THE FORMULA 